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Antidiabetic and Hypoglycemic Effectsof Syzygium cumini (Black Plum)A.R. Shivashankara, A.N. Prabhu, P.P. Dsouza, B.R.V. Baliga,M.S. Baliga, P.L. PalattyFather Muller Medical College, Mangalore, Karnataka, India

ABBREVIATIONSAGEs Advanced glycation end products

CAT Catalase

GSH Reduced glutathione

GST Glutathione S-transferase

H2O2 Hydrogen peroxide

LPO Lipid peroxidation

NIDDM Noninsulin-dependent diabetes mellitus

SOD Superoxide dismutase

1. INTRODUCTION

Diabetes mellitus, characterized by chronic hyperglycemia and disturbances in the

carbohydrate, fat, and protein metabolism, results from either impaired insulin secretion

(type 1 diabetes mellitus) or insulin action (type 2 diabetes mellitus) or at times both

(Andrew, 2000). Diabetes is a disease as old as mankind, and ancient literatures dating

back to first century BC have documented its existence in different civilizations. In spite

of the tremendous progress achieved in medical sciences in the last century, the complete

cure and the management of diabetes mellitus are still absent.

Recent information suggests that diabetes is today the world’s largest endocrine

disorder, and estimates are that it affects almost 10% of the population (WHO, 2009).

Approximations are that worldwide, nearly 285 million people are suffering from

diabetes and that annually around 3.2 million deaths are attributed to it. It is expected

that the number will increase to more than 438 million by the year 2030, and with

disproportionate numbers in the developing countries like India, China, Indonesia,

Japan, Pakistan and Bangladesh, that have limited resources to treat (WHO, 2009).

The other worrying fact is that while most diabetics in the developed countries are

above the age of retirement, in developing countries it is mostly the people between the

35 and 64 years of age that are affected (WHO, 2009). Additionally, the chronic nature

as Dietary Interventions for Diabetesrg/10.1016/B978-0-12-397153-1.00033-0

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538 A.R. Shivashankara et al.

of the disease and the severity of its complications require regular treatment, which af-

fects not only the individuals and their families but also the health care systems of

the world (WHO, 2009). In the milieu of these observations, the World Health

Organization (WHO) has indicated that a global diabetic epidemic is underway

(WHO, 2009).

Excess hyperglycemia causes glucotoxicity, and this leads to the potentially dangerous

long-term side effects like the microvascular impediments that include retinopathy,

nephropathy, and neuropathy, and the macrovascular complications like coronary artery

disease, peripheral artery disease, and cerebrovascular disease. Nonvascular complications

like gastroparesis, infections, and skin changes are also common (Andrew, 2000).

These complications require regular medical attention and at times may require

prolonged hospitalization. The mechanism by which hyperglycemia precisely causes

the observed organ dysfunction is unknown; however, activation of protein kinase C,

formation of advanced glycosylation end products, increased sorbitol production,

activation of hexosamine pathway, and production of reactive oxygen species and

reactive nitrogen species are observed to contribute toward endothelial dysfunction

and cellular damage (Andrew, 2000).

2. CLINICAL MANAGEMENT OF DIABETES

Since its discovery in the early 1960s, the use of insulin has been the mainstay in

the treatment of diabetes. Insulin is extremely useful in the treatment of type 1

diabetes, where its synthesis is compromised. It is also effective when combined

with other hypoglycemic agents in the treatment of type 2 diabetes when other mo-

dalities are ineffective. However, the development of severe hypoglycemia and

localized lipoatrophy at the site of injection complicates the management

(Andrew, 2000).

On a comparative note, the clinical management of type 2 diabetes is complicated and

is used either as monotherapy or in combination to achieve better glycemic regulation.

The use of secretagogs like sulfonylureas and meglitanides is associated with

hypoglycemia and weight gain; metformin to cause lactic acidosis and to aggravate renal

failure; thiazolidonediones to cause fluid retention, cause weight gain, and increase the

risk of fracture; alpha glucosidase inhibitors to cause abdominal discomfort, flatus,

diarrhea, jaundice, and cholestasis; glucagon like peptide (GLP 1) analogs to cause

nausea, pancreatitis, and severe allergic reactions; and amylin agonist to cause nausea

and hypoglycemia (Andrew, 2000).

In view of these observations, discovering newer antidiabetic agents especially

from herbal sources, used in the various alternative and complementary systems of med-

icines that recognize the disease condition and have medications subscribed, is useful

539Antidiabetic and Hypoglycemic Effects of Syzygium cumini (Black Plum)

(Grover et al., 2000, 2002; Mukherjee et al., 2006). The advantages of these plants over

modern medicines are that most of the traditional medicines are plant based and

comparatively cheaper, orally administrable, possess fewer side effects, and have easy

acceptability (Grover et al., 2002; Mukherjee et al., 2006).

3. AYURVEDA AND DIABETES

Ayurveda, which in Sanskrit means knowledge of life (ayu¼ longevity and

veda¼knowledge), is the traditional Indian medical system of medicine. It has been

practiced for more than 5000 years in the Indian subcontinent and is still an integral part

of the Indian culture and materia (Mukherjee et al., 2006). The early practitioners of

Ayurveda were aware of diabetes mellitus and the renowned texts of Ayurveda like

Charaka Samhita (1000 BC), Sushruta Samhita (600 BC), and subsequent works refer

to this disease under the term Madhumeha or Ikshumeha (‘madhu’ meaning sweet/

sweetness and ‘meha’ excessive urination). Detailed descriptions of pathogenesis,

prevention, and management of diabetes are found in the ancient literatures of Ayurveda

(Grover et al., 2002; Mukherjee et al., 2006).

Ayurveda treats diabetes by advocating a balanced and holistic multimodality

approach consisting of change of life style, exercise (yoga), and administering medications

made from various herbs like Gymnema sylvestre, Momordica charantia, Aegle marmeloes,

Swertia chirayita, Syzigium cumini, and Trigonella foenum graecum that are now reported

to possess antihyperglycemic and antidiabetic actions in various experimental systems

of studies, validated and followed in the modern system of medicine (Grover et al.,

2002; Mukherjee et al., 2006).

4. SYZYGIUM cumini AS ANTIDIABETIC PLANT OF IMPORTANCE

S. cumini Lam. Skeels (Syn. Eugenia jambolana Lam; S. jambolanu DC) (Figure 42.1), an

evergreen tree belonging to family myrtaceae, is one of the most important medicinal

plants used in the treatment of diabetes in Ayurveda and in the various folk systems of

Jamun fruit Jamun seed Jamun leaf

Figure 42.1 Photograph of Jamun fruit, seed, and leaf.


medicine in Southeast Asia. Jamun is also used in the treatment of diabetes in the Unani,

Siddha, Srilankan, and Tibetan and in the Homeopathy systems of alternative and com-

plementary medicine (International Academy of Classical Homeopathy, 2010; Sagrawat

et al., 2006). Additionally, Jamun is also a major constituent of many marketed antidia-

betic formulations and some of the well-known formulations which contain Jamun

include diabecon, diasulin, pancreatic tonic 180cp, dia-care, diabeta, hyponidd, and

diashis (Subash Babu and Prince, 2004).

4.1 Botanical Aspects of JamunHistorically, the Jamun tree was exclusive to the Indian subcontinent but is today found

growing throughout the Asian subcontinent, Eastern Africa, South Africa, Madagaskar,

and in the warmer regions of USA in states like Florida. The fruit of E. jambolana is called

by different names such as Jamun, black plum, Indian blackberry, jambu, and jambool

(Warrier et al., 1996). The tree grows up to a height of 50 ft and has sufficiently large

canopy. The young barks are pale brown in color, while the mature are slightly dark

brown, scaly and at times peel off. The leaves are elliptic to broadly oblong, smooth,

glossy, leathery, and fibrous in nature (Warrier et al., 1996).

The tree flowers and fruits once a year, which in the Indian subcontinent is during the

month of June–July. The flowers are sessile, small (7–12 mm), white in color, fragrant,

and with thin membranous petals. They are arranged mostly in threes and appear usually

from the scars of the fallen leaves (Warrier et al., 1996). The fruits are found in clusters of

4–20, and the process of fruiting from the flowering stage takes around 2 months to com-

plete. The Jamun fruits present in a bunch, do not ripen all at once, and drop off when

fully ripe. Each fruit is round, oblong, or ellipsoid, 1/2 to 2 in. long with a centrally

placed large seed. The raw fruits are green in color and as they mature turn to light ma-

genta and then to dark purple or black when fully ripe. The fully ripe fruit has a com-

bination of sweet, mildly sour, and astringent flavor and imparts purple color to the

tongue of the consumer (Warrier et al., 1996).

4.2 Phytochemistry of JamunJamun plant is known to possess diverse phytochemicals, most of which are observed

to be of beneficial effects to health. The stem bark is reported to possess friedelin,

friedelan-3-a-ol, betulinic acid, b-sitosterol, kaempferol, b-sitosterol-D-glucoside, gallicacid, ellagic acid, gallotannin and ellagitannin, and myricetine (Sagrawat et al., 2006). The

leaves are known to contain b-sitosterol, betulinic acid, mycaminose, crategolic (maslinic)

acid, n-hepatcosane, n-nonacosane, n-hentriacontane, noctacosanol, n-triacontanol,

n-dotricontanol, quercetin, myricetin, myricitrin, and the flavonol glycosides myricetin

3-O-(400-acetyl)-a-L-rhamnopyranosides (Sagrawat et al., 2006). The flowers are observed

to contain oleanolic acid, ellagic acids, isoquercetin, quercetin, kampferol, and myricetin

(Sagrawat et al., 2006).


Studies have shown that the pulp of Jamun contains anthocyanins, delphinidin,

petunidin, and malvidin-diglucosides. These compounds are responsible for their bright

purple color (Sagrawat et al., 2006; Sharma et al., 2008a,b; Veigas et al., 2007). The seeds

are the most studied plant part and are reported to contain jambosine, gallic acid, ellagic

acid, corilagin, 3,6-hexahydroxy diphenoylglucose, 4,6-hexahydroxydiphenoylglucose,

1-galloylglucose, 3-galloylglucose, quercetin, and b-sitoterol (Sagrawat et al., 2006). Theessential oil is reported to contain the phytochemicals pinocarveol, a-terpeneol,myrtenol, eucarvone, muurolol, a-myrtenal, 1, 8-cineole, geranyl acetone, a-cadinol,and pinocarvone. Some of the phytochemicals are depicted in Figure 42.2.

4.3 Traditional UsesAll parts of the Jamun and the seeds in particular have a long history of medicinal

use in the various traditional and folk systems of medicines in countries where it

grows. The fruits are considered to be tonic, astringent, carminative, and useful in

spleen diseases. The fruits and seeds are also used to treat pharyngitis and ringworm

infection. The fruits are acrid and sweet, cooling, dry, and astringent to bowels (Warrier

et al., 1996). Seeds are astringent, diuretic, and stop urinary discharge (Warrier et al., 1996).

The bark of the plant is astringent, sweet, refrigerant, carminative, antihelmintic, febrifuge,

constipating, stomachic, antibacterial, diuretic, and digestive (Warrier et al., 1996). The

leaves have been extensively used to treat diabetes, constipation, leucorrhoea, stomachalgia,

fever, gastropathy, strangury, dermopathy and to inhibit blood discharges in the feces

(Warrier et al., 1996). The leaves are considered to possess antibacterial effects and are used

to strengthen the teeth and gums (Warrier et al., 1996).

In the Ayurvedic system of medicine, Jamun is considered good for treating sore

throat, bronchitis, asthma, dysentery, and diabetes mellitus. In India, decoction of kernels

Jamun is used as household remedy for diabetes. In the Siddha system of medicine, Jamun

is recognized to be hematinic, semen promoting, and to reduce the excessive heat of the

body (Warrier et al., 1996). According to the Unani system of medicine, it acts as liver

tonic, enriches blood, strengthens teeth and gums, and forms good lotion for removing

ringworm infection of the head. The ashes of the leaves are used as a dentrificant to

strengthen the teeth and the gums (Warrier et al., 1996). The seeds are astringent, di-

uretic, stop urinary discharge, and are a remedy for diabetes. The barks also possesses

wound-healing properties. The homeopathic system of medicine, originally native to

Europe, also uses Jamun to treat various ailments, including diabetes.

5. ANTIDIABETIC EFFECTS OF JAMUN

Jamun has been thoroughly investigated for its antidiabetic effects during the last

127 years. Many experimental studies with rodents have shown that the seed, fruit,

and bark of Jamun possess antidiabetic effects (Gohil et al., 2010; Helmstadter, 2007,

HO

HOHO

HOHO

HO

O+

HO

HO

OH

OH

Anthocyanin

PetunidinEllagic acid Gallic acid

Delphinidin MalvidinOH

OH

OH

OH

OH

OHOH

OH

OH

OH

OH

OH O

O

O

O

O

O

O+

O

O

OH

OH

OCH3

CH3

CH3OH

O

HO

HO

HO

HO

HO

OH

OH

OH

OH

OH

OH

H3C

H3C

CH3

OCH3

COOHCH3

CH3

OH

OH

OH

OH

OH

OH

OH

OH

OHOH

O

O

O

Myricetin

Betulinic acid Caffeic acid Ferulic acid

Kaempherol Quercetin

O O

O O

O

Figure 42.2 Important phytochemicals present in Jamun.


2008; Sharma et al., 2009), while the leaf is devoid of these effects (Pepato et al., 2001).

Jamun exhibited hypoglycemic action similar or sometimes even better than the oral

hypoglycemic drugs (Sahana et al., 2010; Saravanan and Pari, 2007; Subash Babu and

Prince, 2004).

Administering Jamun is observed to decrease the fasting and postprandial blood glu-

cose levels by about 30%, in these studies. Jamun seeds and their extracts, both polar and

nonpolar, have been reported to be effective. Fruit pulps when administered as lyoph-

ilized powder too were proficient. Jamun was capable in preventing hyperglycemia and


diabetic complications in laboratory animals. The dosage in these studies ranged from 25

to 2000 mg kg�1, and the duration of treatment was from a single administration to daily

for up to 6 weeks. Consequently, a few studies also suggest that Jamun possesses antihy-

perglycemic action in humans suffering from diabetes (Gohil et al., 2010; Helmstadter,

2008; Sahana et al., 2010; Sharma et al., 2009).

6. USE OF JAMUN SEEDS IN THE TREATMENT OF DIABETES,PRECLINICAL STUDIES

Innumerable experimental studies in the past two decades have shown that the seed of

Jamun possesses antihyperglycemic effects (Achrekar et al., 1991; Rathi et al., 2002;

Ravi et al., 2004a,b,c, 2005; Sharma et al., 2003, 2008a,b; Sridhar et al., 2005).

The Jamun seed, which is the ethnomedically recommended plant part, has been

studied extensively, and the observations seen from the scientific studies validated

the traditional observations.

Studies with alloxan-induced diabetic rabbits have shown that ethanolic extract of the

seeds was effective in decreasing hyperglycemia in the subdiabetic and mildly diabetic

rabbits, but it was ineffective against severely diabetic rabbits. Administering the extract

(100 mg kg�1 body weight) orally to subdiabetic rabbits for 1 day, mildly diabetic for

7 days, and severely diabetic rabbits for 15 days showed significant decrease in the fasting

blood glucose during glucose tolerance test. In addition, a significant decrease in the

glycosylated hemoglobin levels and a concomitant increase in the concentration of serum

insulin, and in the levels of liver and muscle glycogen were also observed. The histopath-

ological studies of liver, pancreas, and aorta in alcoholic extract treated diabetic groups

showed almost normal appearance (Sharma et al., 2003).

Sharma et al. (2009) purified hypoglycemic principles from Jamun seeds and one

such principle named as LH II was shown to contain saturated fatty acid and sterol.

Administration of LH-II orally at a dose of 10 mg kg�1 resulted in significant decrease

in fasting blood glucose at 90 min, seventh day, and fifteenth day in diabetic rabbits.

Glycosylated hemoglobin was significantly decreased in severely diabetic rabbits after

15 days of treatment. Plasma insulin levels were significantly increased. To further val-

idate these observations, mechanistic studies in the in vitro systems with pancreatic islets

have shown a threefold increase in insulin levels as compared with untreated animals.

There was an increase in the activity of key enzymes of glycolysis and decrease in the

activity of key enzymes of gluconeogenesis. Liver and muscle glycogen content were also

increased (Sharma et al., 2009).

The flavonoid-rich extract obtained from seeds of Jamun is also observed to be an

efficient antihyperglycemic agent in the streptozotocin-induced diabetic rats (Sharma

et al., 2008a). In vitro study validated that the culturing pancreatic cells with flavonoids

stimulated 16% release in insulin, thereby confirming its ethnomedicinally presumed


secretagog effects. The extract also possessed hypolipidemic action and decreased the

levels of low-density lipoprotein (LDL) and triglycerides and increased the high-density

lipoprotein (HDL) levels over untreated diabetic rats (Sharma et al., 2008a).

The rate of glycogen biosynthesis levels of glucose homeostatic enzymes (glucose-

6-phosphatase, and hexokinase) was also enhanced when compared with the diabetic co-

horts (Sharma et al., 2008b). Jamun seed and pulp extract stimulated the release of insulin

from the cultured Langerhans cells from both normal and diabetic rats, with better effects

seen in the cells from the normoglycemic animals (Achrekar et al., 1991). The pulp and

seed extracts were also found to inhibit the hepatic and renal insulinase activity in a con-

centration-dependent manner (Achrekar et al., 1991).

In addition to decreasing hyperglycemia and hyperinsulinemia, animal studies have

also shown that Jamun seeds prevented the diabetes-induced secondary complications

like nephropathy, neuropathy (Grover et al., 2002), gastropathy (Grover et al., 2002),

and diabetic cataract (Rathi et al., 2002) and also decreased peptic ulceration (Chaturvedi

et al., 2009). These properties are useful in the management of the hyperglycemia-induced

complications and in improving the quality of life of the patients.

The alcoholic extract of Jamun was shown to restore serum glutamic oxaloacetate

transminase and serum glutamic pyruvate transminase activities and serum urea, total

protein, and albumin concentrations in streptozotocin diabetic rats, in a dose- and

duration-dependent manner. These observations suggest that Jamun is useful in prevent-

ing structural and functional impairment of liver and kidney, in diabetes. The beneficial

effects of Jamun in 500 mg kg�1 dose in streptozotocin diabetic rats were comparable to

that of glibenclamide (300 mg kg�1), a standard oral hypoglycemic drug used in clinical

practice (Sundaram et al., 2009). Studies have also shown that mycaminose (50 mg kg�1),

isolated from the seeds of Jamun, produced significant reduction in blood glucose level

against streptozotocin-induced diabetes in rats (Kumar et al., 2008).

Administration of different doses of alcoholic and aqueous extracts of Jamun seed to

fructose-induced type 2 diabetic rats was observed to cause concentration-dependent

beneficial effects. Feeding fructose for 15 days increased the serum glucose, insulin levels,

and the triglycerides levels marginally when compared with the normal controls (Vikrant

et al., 2001). Treatment with 400 mg day�1 of aqueous extracts of Jamun for 15 days

substantially prevented hyperglycemia and hyperinsulinemia induced by a diet high in

fructose, suggesting it to be of use in type 2 diabetes (Vikrant et al., 2001).

7. USE OF JAMUN FRUIT PULP IN DIABETES TREATMENT

The fruits of Indian Jamun have been shown to have antihyperglyciemic properties

(Achrekar et al., 1991; Sharma et al., 2006; Sundaram et al., 2009). The oral antihyper-

glycemic effect of water and ethanolic extracts of the fruit pulp of Jamun was investigated

in alloxan-induced rabbits (Sharma et al., 2006). Water extract was found to be more


effective than the ethanolic extract in reducing the fasting blood glucose and improving

blood glucose in the glucose tolerance test. Chromatographic purification of the water

extract yielded two hypoglycemic fractions. Decrease in fasting blood glucose, improved

glucose tolerance, and increase in the plasma insulin levels were seen in both moderately

diabetic and severely diabetic rabbits. In vitro studies with pancreatic islets showed that the

insulin release was nearly two and half times more than that in untreated diabetic rabbits

(Sharma et al., 2006).

The mechanism of action of FIII fraction appears to be both pancreatic by stimulating

release of insulin and extra pancreatic by directly acting on the tissue (Sharma et al., 2006).

Pepato et al. (2005) investigated the antidiabetic effects of Brazilian Jamun fruit. They

found that, when compared to the untreated controls, rats treated with the lyophilized

fruit pulp showed no observable difference in body weight, food or water intake, urine

volume, glycemia, urinary urea and glucose, hepatic glycogen, or on serum levels of total

cholesterol, HDL cholesterol, or triglycerides. This lack of any apparent effect on diabetes

was attributed to the regional ecosystem where the fruit was collected and to the severity

of the induced diabetes (Pepato et al., 2005).

8. JAMUN BARK IN DIABETES TREATMENT

Dried bark at a dose of 5 mg/20 gmouse caused significant decrease in glucose levels after a

glucose tolerance testing (Villasenor and Lamadrid, 2006). Oral or intraperitoneal admin-

istration of bark extract exhibited antidiabetic activity by significantly lowering blood glu-

cose and urine sugar levels in diabetic rats and improving glucose tolerance. Additionally,

diabetic rats treated with bark extract had elevated levels of plasma insulin and C-peptide.

Therewas also a significant decrease in the level of sialic acid and elevated levels of hexose,

hexosamine, and fucose in the liver and kidney of diabetic rats, whichwas reversed by bark

extract treatment. As compared with glibenclamide, bark extract had better antidiabetic

effects (Saravanan and Leelavinothan, 2006; Saravanan and Pari, 2007).

9. HUMAN TRIALS ON ANTIDIABETIC EFFECT OF JAMUN

There have been very few studies on human volunteers in the post-1945 era, but these

studies have shown promising results. Srivastava et al. (1983) administered 4–24 g of the

seed powder to 28 diabetic patients and observed a reduction in the mean fasting and

postprandial blood sugar levels. Later, Kohli and Singh (1993) have also observed that

administering 12 g of the Jamun seed powder in three divided doses for 3 months to

30 patients with ‘uncomplicated’ noninsulin-dependent diabetes mellitus (NIDDM)

caused a moderate hypoglycemic effect. The effect of Jamun was comparable to that

of chlorpropamide, and it caused considerable relief by ameliorating symptoms like poly-

urea, polyphagia, weakness, and weight loss. In this study, no side effects were observed,


and this may be possibly due to the fact that the powder was administered thrice a day

(Kohli and Singh, 1993).

Recently, in an open labeled randomized parallel designed controlled study with

freshly diagnosed, 15 type 2 diabetes mellitus patients, Sahana et al. (2010) observed that

administering the standardized seed powder caused a significant decrease in the fasting

blood sugar, insulin resistance, and increase inHigh-density lipoprotein (HDL) cholesterol

at the end of the third month (when comparedwith the baseline). However, there was no

significant reduction in the post-prandial blood sugar (PPBS) and glycated hemoglobin

(hemoglobinA1c,HbA1c,A1C,orHb1c) at the endof third and sixthmonth,when com-

pared to the baseline. There was no change in the triglyceride, total cholesterol, and low-

density lipoprotein (LDL) LDL levels (Sahana et al., 2010).

10. MECHANISMS OF ACTION

Diabetes mellitus is a multifactorial disorder involving genetic influence and effects of

environmental factors. Type 1 diabetes mellitus involves genetic basis with autoimmune

destruction of pancreatic islet beta cells triggered by viral infections. Type 2 diabetes

mellitus has the involvement of many genes and multiple environmental factors. Insulin

resistance, decreased insulin sensitivity, impaired glucose uptake, hyperglycemia, and

dyslipidemia are the biochemical features of type 2 diabetes mellitus. The long-term

complications of DM include retinopathy, neuropathy, and nephropathy.

Various mechanisms have been proposed for the antidiabetic actions of Jamun. These

mechanisms include stimulation of pancreatic insulin secretion (Achrekar et al., 1991;

Gohil et al., 2010; Saravanan and Leelavinothan, 2006; Sharma et al., 2006, 2009; Sridhar

et al., 2005), restoration of beta cell architecture (Achrekar et al., 1991; Gohil et al., 2010;

Sharma et al., 2003), reduction of oxidative stress and antioxidant action (Ravi et al.,

2004a,c; Subash Babu and Prince, 2004), and amelioration of dyslipidemia (Gohil

et al., 2010; Sharma et al., 2008a,b).

Other mechanisms suggested are inhibition of the human peroxisome proliferator-

activated receptor (PPAR) gamma (Rau et al., 2006), upregulation of the glucose

transporter type 4 (GLUT-4) (Anandharajan et al., 2006), rise in cathepsin-B activity

(Achrekar et al., 1991), inhibition of extrahepatic insulinase activity, development of

insulin positive cells from the pancreatic duct epithelial cells (Schossler et al., 2004), and

increase in glycogen content in liver and muscle (Achrekar et al., 1991; Sharma et al.,

2003, 2008a). Jamun also caused an increase in the activity of key enzymes of glycolysis

and decrease in the activity of important enzymes of gluconeogenesis (Sharma et al., 2009).

10.1 Jamun Stimulates Pancreatic Insulin Secretion and Restores andRegenerates Beta Cell Architecture (Secretagog Effect)

Optimal pancreatic beta-cell function is essential for the regulation of glucose homeosta-

sis, and its impairment leads to the development of diabetes. Insulin and C-peptide are the


products of the enzymatic cleavage of proinsulin and are secreted into the circulation in

equimolar concentrations. Serum levels of insulin and C-peptide are indicators of

beta cell function. Few studies have demonstrated that Jamun stimulates secretion of

pancreatic insulin (Achrekar et al., 1991; Gohil et al., 2010; Ravi et al., 2004a,b; Sharma

et al., 2006; Sridhar et al., 2005). Increased C-peptide on treatment with Jamun bark

extract has been observed in diabetic rats (Saravanan and Leelavinothan, 2006; Saravanan

and Pari, 2007).

Jamun administration is reported to restore the architecture of the pancreatic beta cell

in diabetic experimental animal cells (Achrekar et al., 1991; Gohil et al., 2010; Sharma

et al., 2003). Additionally, it also increases plasma insulin levels by converting proinsulin

to insulin possibly through pancreatic cathapsin B and its secretion (Bansal et al., 1981).

Jamun extract is also reported to inhibit the insulinase activity from the liver and kidney

(which are the main sites for insulin extraction), thereby suggesting that its protective

effects are also mediated by the extrapancreatic pathways (Achrekar et al., 1991; Gohil

et al., 2010; Sharma et al., 2008a,b).

Phytochemical examinations have confirmed that Jamun contains flavonoids and

other polyphenolics, and it is possible that these compounds could act separately or

synergistically to cause the hypoglycemic effect. To substantiate this, flavonoids are

shown to regenerate the damaged pancreatic beta cells in diabetic animals (Vessal

et al., 2003). Anthocyanins, the natural colorants, have also been shown to stimulate

insulin secretion from rodent pancreatic b-cells in vitro (Jayaprakasam et al., 2005).

10.2 Jamun Reduces the Oxidative Stress and Improves AntioxidantStatus

Oxidative stress refers to a condition of increased generation of free radicals and depletion

of antioxidant defense systems. Experimental evidence suggests the involvement of free

radicals in the onset of diabetes and more importantly in the development of diabetic

complications. Persistent hyperglycemia in the diabetic patients leads to generation of

oxidative stress due to autooxidation of glucose, nonenzymatic glycosylation of body

proteins, and polyol pathway. The autooxidation of glucose involves spontaneous

reduction of molecular oxygen to superoxide and hydroxyl radicals, which are highly

reactive and interact with all biomolecules. They also accelerate the formation of

advanced glycation end products (AGEs) and impair synthesis, regeneration, and

functioning of antioxidants. Together these mechanisms contribute to the secondary

complications observed in diabetes (Yan et al., 2008).

Benherlal and Arumughan (2007) evaluated the antioxidant effects of the ethanolic

extract of the fruit pulp, kernel, and seed coat in various in vitro assays (diphenyl-1-picryl-

hydrazyl (DPPH), OH and O2•�) with gallic acid, quercetin, and trolox as reference

molecules. The authors observed that in the DPPH scavenging assay the kernel extract

was better than the seed coat and pulp extract but less effective than the reference


molecules. However, in the superoxide radical scavenging activity the kernel extract was

six times more effective than trolox and three times more than catechin.

In hydroxyl radical scavenging assay, the kernel extract was comparable to the

effect of catechin (Benherlal and Arumughan, 2007). The methanol–formic acid (9:1)

extract of the fruit (Reynertson et al., 2008), the hydroethanolic extract of the seed

(Raquibul-Hasan et al., 2009), and anthocyanin-rich fruit peel extract (Veigas et al.,

2008) have all been reported to be potent free radical scavengers in the DPPH scavenging

assay. The hydrolyzable and condensed tannins in the fruit are also reported to possess

antioxidant activity in the DPPH radical scavenging and fluorescence recovery after

photobleaching assays (Zhang and Lin, 2009). The organic extract of the leaf (metha-

nol-dichloromethane extract) as well as the hydroethanolic extract of the seed are

reported to be a scavenger of nitric oxide in vitro (Jagetia et al., 2005).

Studies by Banerjee et al. (2005) have shown that the fruit skin of Jamun possesses

antioxidant effects as confirmed by results from the hydroxyl radical-scavenging assay, su-

peroxide radical-scavenging assay, DPPH radical-scavenging assay, and lipid peroxidation

assay with egg yolk as the lipid-rich source. The anthocyanin-rich fruit peel extract is also

observed to be an effective reducing agent (Veigas et al., 2008). Recently, Bajpai et al.

(2005) have also observed that the hydromethanolic extract of the Jamun seed was effective

in scavenging (90.6%) free radicals as evaluated in the autooxidation of b-carotene and

linoleic acid assay. The authors observed that there was a direct correlation between the

free radical scavenging effect and the presence of high total phenolic content in the extract

and that this contributed to the observed effects (Bajpai et al., 2005).

Animal studies have also shown that administering Jamun decreased the levels of lipid

peroxides in the stomach of animals subjected to ulcerogenic treatments (Chaturvedi

et al., 2009) in the brain, liver, kidneys, and serum of diabetic animals (Ravi et al.,

2004a,c; Subash Babu and Prince, 2004).

10.3 Jamun Improves Glucose Utilization and Maintains GlucoseHomeostasis

In the postprandial state, insulin promotes the uptake of glucose by tissues, glycolysis,

oxidation, and glycogenesis. Studies suggest that administering Jamun increases glycogen

content in the liver and muscle cells of diabetic animals (Achrekar et al., 1991; Gohil

et al., 2010; Ravi et al., 2003; Sharma et al., 2003, 2008a,b), increases the activities of

enzymes crucial for glycogenesis and glycolysis, and concomitantly decreases enzymes

involved in gluconeogenesis.

10.4 Jamun Prevents Alterations in Glycation Status and Formation ofAGEs

The high incidence of vascular complications in patients with diabetes mellitus has

prompted researchers to look for a relationship between vascular dysfunction and


diabetes mellitus. Several hypotheses relating to hyperglycemia have been proposed: the

sorbitol hypothesis, the diacyl glycerol pathway, the nonenzymatic glycation of proteins,

and an alteration of the redox potential. A long exposure to hyperglycemia leads to the

glycosylation of proteins and lipoproteins by a nonenzymatic pathway called as Maillard

reaction. The nonenzymatic glycosylation, or glycation, results in the formation of

different classes of heterogeneous sugar–protein adduct collectively called AGEs (Yan

et al., 2008).

AGEs generate reactive oxygen intermediates by autooxidation. They are responsible

for diabetic microvascular and macrovascular complications. Blood levels of glycated

proteins and their products such as glycated hemoglobin, glycated albumin, and

fructosamine are used as indices of glycemic control in diabetics. Studies have shown that

the blood levels of glycated hemoglobin in experimental diabetic animals decreased on

administering Jamun (Sharma et al., 2006, 2008a,b, 2009). However, similar observation

was unseen in glycated hemoglobin levels of humans administered with Jamun (Sahana

et al., 2010).

Levels of glycoconjugates such as protein-bound sialic acid, protein-bound fucose,

and protein-bound hexosamines are known to increase with progression of diabetic

complications. Diabetic rats showed increased or decreased levels of sialic acid and

increased levels of total hexoses, fucose, and hexosamines in plasma, liver, kidney, heart,

and brain (Saravanan and Pari, 2007). Treatment with Jamun bark extract was effective in

restoring the levels of sialic acid, hexose, hexosamine, and fucose in plasma, liver, and

kidney of diabetic rats (Saravanan and Pari, 2007). The observed effect of Jamun bark

extract on reversing the adverse effects of hyperglycemia provides an insight into the

pathogenesis of diabetic complications and may be used to advantage in therapeutic

approaches.

10.5 Jamun Has Ameliorating Effect on Dyslipidemia in DiabetesDyslipidemia characterized by increased levels of triglycerides, total cholesterol, and LDL

and decreased level of HDL is an important biochemical abnormality of diabetes mellitus.

Free radicals target lipoproteins, especially LDL, to cause their oxidation. Oxidized LDL

is implicated in the etiopathogenesis of atherosclerosis and vascular complications of DM

and cardiovascular diseases (Vikrant et al., 2001).

Preclinical studies have shown that administering Jamun seeds and fruits decreased

LDL cholesterol, triglycerides, and total cholesterol and increased HDL cholesterol

in diabetic rats or rabbits (Helmstadter, 2008; Sharma et al., 2006, 2008a,b; Vikrant

et al., 2001). In the case of human studies, some observations suggest beneficial

effects in amelioration of dyslipidemia (Helmstadter, 2008) while others have been

contradictory (Sahana et al., 2010).


10.6 Jamun Inhibits Alpha-GlucosidasesAlpha-glucosidase inhibitors (acarbose, migitol, and voglibose), which inhibit the

digestion of carbohydrates, are used to establish greater glycemic control over hypergly-

cemia in diabetes mellitus type 2, particularly with regard to postprandial hyperglycemia.

They may be used as monotherapy in conjunction with an appropriate diabetic diet and

exercise, or they may be used in conjunction with other antidiabetic drugs. These

medications do not stimulate pancreas to produce insulin, and they lower blood sugar

when used in combination with other oral medications for diabetes or with insulin.

Recently, in vitro studies by Ahmed et al. (2009) have shown that the Jamun

extract significantly inhibited the a-amylase, a-glucosidase, and sucrase activities in a

dose-dependent manner. The heat treatment of the sample resulted in a significant

increase in the a-amylase inhibitory activity of the sample, while a marginal increase

in the a-glucosidase and sucrase inhibitory activities was observed. These findings

emphasize that inhibition of carbohydrate hydrolyzing enzymes is one of the mechanisms

through which Jamun exerts its hypoglycemic effect in vivo (Ahmed et al., 2009).

10.7 Jamun Activates Peroxisomal Proliferator-Activated ReceptorsThe PPARs are a group of nuclear receptor proteins important in the regulation of

carbohydrate, lipid, and protein metabolism. They are expressed highly in the adipose

tissue, and activation of PPARg induces adipocyte differentiation and lipid accumulation

by modulating numerous genes regulating adipogenesis, lipid uptake, and lipid metabo-

lism (Berger, 2005). The hypolipidemic fibrates activate PPARa, and the antidiabetic

glitazones activate PPARg. The fibrate-type hypolipidemic drugs can induce the

expression of genes participating in lipid catabolism such as fatty acid uptake and binding,

fatty acid oxidation in microsomes, peroxisomes, and mitochondria, and lipoprotein

assembly and transport. Likewise, thiazolidinediones are PPARg ligands, and the

antidiabetic effects exerted by this type of drugs are believed to be mediated by PPARg(Libby and Plutzky, 2007).

A growing body of evidence indicates that herbal compounds influence PPARs and

mediate their protective effects (Rau et al., 2006). Rau et al. (2006) screened a variety of

ethanolic extracts, obtained from traditionally used herbs including Jamun, for PPAR

activation. They observed that Jamun activated both PPARa and PPARg. Sharma

et al. (2008a,b) observed that the hypoglycemic and hypolipidemic actions of Jamun

were mediated through dual mechanisms (1) by upregulation of both the peroxisome

proliferator-activated receptors (PPARa and PPARg) up to about three- to fourfolds

(over control) and (2) by their capacity to promote adipocyte differentiation. Together,

these observations clearly suggest the beneficial effects of Jamun.


11. CONCLUSIONS

Jamun has been used to treat diabetes for centuries, and scientific studies carried out in the

past few decades have confirmed that the seed is most effective and is useful in both

insulin-dependent and noninsulin-dependent diabetes. Reports also suggest it to be

effective in reducing the production of glucose, in inducing utilization of glucose, and

of use in preventing/retarding diabetic complications. Mechanistic studies indicate that

Jamun possesses free radical scavenging and antioxidant effects, prevents lipid peroxida-

tion, regenerates the b-cells, prevents alterations in glycation status and formation

of AGEs, improves glucose utilization and maintains glucose homeostasis, activates

peroxisomal PPARs, inhibits alpha-glucosidases, and ameliorates dyslipidemia. These

activities are beneficial in reducing hyperglycemia and in preventing/reducing the

secondary complications of diabetes. Although Jamun has been propounded as an

effective antidiabetic agent in both traditional and animal studies, the clinical trials

performed with small sample size have been inconclusive. The antidiabetic action of

Jamun includes the combined effect of acarbose, meglutude, insulin, lovastatin, and

vitamin E. Future studies should be aimed at performing randomized double-blinded

clinical studies with a large sample size and a standardized extract with suitable

controls. The observation from these studies will help in understanding and validating

the traditional observations.

ACKNOWLEDGMENTSThe authors dedicate this chapter to Prof Meera Pai, Former Head of Department of Pharmacology,

Kasturba Medical College, Mangalore, India for her seminal studies on the antidiabetic effects of Jamun.

The authors are grateful to Rev. Fr. Patrick Rodrigus (Director), Rev. Fr. Denis D’Sa (Administrator, Father

Muller Medical College), and Dr. Jayaprakash Alva (Dean, Father Muller Medical College) for their

unstinted support. Due to space constraints, many of the published articles could not be quoted, and the

authors express their sincere regret to their esteemed colleagues.

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